Asthma is a chronic inflammatory disease that affects millions of people in the US alone. It is characterized by mucus hypersecretion, airway hyperresponsiveness, and airway wall remodeling that results in variable airway obstruction in genetically susceptible individuals. Our laboratory has demonstrated by tissue-specific knock-out that the STAT3 transcription factor is essential for the development of inflammation, AHR and remodeling in the house dust mite model of asthma. Further, we have found that inhibition of STAT3 by small molecules and decoy oligonucleotides similarly blocked HDM-induced airway inflammation in vivo, suggesting that STAT3 may be a feasible therapeutic target for treatment of allergic inflammation. Here we propose to determine the mechanisms by which STAT3 contributes to these asthmatic features. While multiple cell types, are critical in the allergic response, the bronchial epithelium bridges the external and internal environments and is one of the first points of contact for allergens, and thus likely plays a crucial role in establishing airway inflammation. In addition, it is postulated that the airway epithelium in asthmatics has increased susceptibility to injury, which promotes a repair response and airway wall remodeling. Airway wall remodeling may contribute to the chronic airflow obstruction and AHR seen in some asthmatics despite maximal medical therapy. As a result it is critical to elucidate the molecular mechanisms that underlie remodeling, as well as determine the relation of remodeling to inflammation. We have established that STAT3 deletion in the airway epithelium results in significantly decreased production of both Th2 cytokines and chemokines in the airway, as well as decreased lung Th2 cells, suggesting that STAT3 is critical for Th2 cell function and trafficking in the lung in response to HDM. The central hypothesis of this proposal is that airway epithelial STAT3 directs allergic inflammation and airway remodeling by producing critical cytokines and chemokines required for immune cell (T cell and dendritic cells) function and recruitment. In addition, STAT3 in airway smooth muscle (ASM) may be critical for airway wall remodeling via its effects on ASM proliferation and survival. The overall objective of this proposal is to define the role(s) of airway epithelial and smooth muscle STAT3 in directing both both inflammation and airway remodeling in a murine model of allergic asthma. Our specific aims are to: 1)To define the mechanisms by which epithelial STAT3 deletion attenuates allergic inflammation during the recall response to HDM;2) To determine the effect of inactivating STAT3 in the airway epithelium on HDM-induced airway wall remodeling and;3) To investigate the role of ASM STAT3 in HDM-induced airway inflammation and/or airway wall remodeling. Information derived from these studies could provide the basis for novel therapeutic targets for patients with asthma and airway wall remodeling.